Pharmaceutical compositions and methods for effecting dopamine release

ABSTRACT

Patients susceptible to or suffering from disorders, such as central nervous system disorders, which are characterized by an alteration in normal neurotransmitter release, such as dopamine release (e.g., Parkinsonism, Parkinson&#39;s Disease, Tourette&#39;s Syndrome, attention deficient disorder, or schizophrenia) are treated by administering an endo or exo form of a 1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane, a 1-aza-2-(3-pyridyl)bicyclo[2.2.2]octane, a 1-aza-2-(3-pyridyl)bicyclo[3.2.2]nonane, a 1-aza-7-(3-pyridyl)bicyclo[2.2.1]heptane, a 1-aza-3-(3-pyridyl)bicyclo[3.2.2]nonane, or a 1-aza-7-(3-pyridyl)bicyclo[3.2.2]nonane.

BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical compositions, andparticularly pharmaceutical compositions incorporating compounds whichare capable of affecting nicotinic cholinergic receptors. The presentinvention also relates to methods for treating a wide variety ofconditions and disorders, and particularly conditions and disordersassociated with dysfunction of the central and autonomic nervoussystems.

Nicotine has been proposed to have a number of pharmacological effects.See, for example, Pullan et al. N. Engl. J. Med. 330:811-815 (1994).Certain of those effects may be related to effects upon neurotransmitterrelease. See for example, Sjak-shie et al., Brain Res. 624:295 (1993),where neuroprotective effects of nicotine are proposed. Release ofacetylcholine and dopamine by neurons upon administration of nicotinehas been reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapieret al., J. Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313(1991) and Vizi, Br. J. Pharmacol. 47:765 (1973). Release ofnorepinephrine by neurons upon administration of nicotine has beenreported by Hall et al., Biochem. Pharmacol. 21:1829 (1972). Release ofserotonin by neurons upon administration of nicotine has been reportedby Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977). Release ofglutamate by neurons upon administration of nicotine has been reportedby Toth et al., Neurochem Res. 17:265 (1992). In addition, nicotinereportedly potentiates the pharmacological behavior of certainpharmaceutical compositions used for the treatment of certain CNSdisorders. See, Sanberg et al., Pharmacol. Biochem. & Behavior 46:303(1993); Harsing et al., J. Neurochem. 59:48 (1993) and Hughes,Proceedings from Intl. Symp. Nic. S40 (1994). Furthermore, various otherbeneficial pharmacological effects of nicotine have been proposed. See,Decina et al., Biol. Psychiatry 28:502 (1990); Wagner et al.,Pharmacopsychiatry 21:301 (1988); Pomerleau et al., Addictive Behaviors9:265 (1984); Onaivi et al., Life Sci. 54(3):193 (1994) and Hamon,Trends in Pharmacol. Res. 15:36.

Various nicotinic compounds have been reported as being useful fortreating a wide variety of conditions and disorders. See, for example,Williams et al. DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev.1(1): 1-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1):79-100(1996), Bencherif et al., JPET279:1413 (1996), Lippiello et al., JPET279:1422 (1996), PCT WO 94/08992, PCT WO 96/31475, and U.S. Pat. Nos.5,583,140 to Bencherif et al., U.S. Pat. No. 5,597,919 to Dull et al.,and U.S. Pat. No. 5,604,231 to Smith et al. Nicotinic compounds areparticularly useful for treating a wide variety of Central NervousSystem (CNS) disorders.

CNS disorders are a type of neurological disorder. CNS disorders can bedrug induced; can be attributed to genetic predisposition, infection ortrauma; or can be of unknown etiology. CNS disorders compriseneuropsychiatric disorders, neurological diseases and mental illnesses;and include neurodegenerative diseases, behavioral disorders, cognitivedisorders and cognitive affective disorders. There are several CNSdisorders whose clinical manifestations have been attributed to CNSdysfunction (i.e., disorders resulting from inappropriate levels ofneurotransmitter release, inappropriate properties of neurotransmitterreceptors, and/or inappropriate interaction between neurotransmittersand neurotransmitter receptors). Several CNS disorders can be attributedto a cholinergic deficiency, a dopaminergic deficiency, an adrenergicdeficiency and/or a serotonergic deficiency. CNS disorders of relativelycommon occurrence include presenile dementia (early onset Alzheimer'sdisease), senile dementia (dementia of the Alzheimer's type),Parkinsonism including Parkinson's disease, Huntington's chorea, tardivedyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety,dyslexia, schizophrenia and Tourette's syndrome.

Senile dementia of the Alzheimer's type (SDAT) is a debilitatingneurodegenerative disease, mainly afflicting the elderly; characterizedby a progressive intellectual and personality decline, as well as a lossof memory, perception, reasoning, orientation and judgment. One featureof the disease is an observed decline in the function of cholinergicsystems, and specifically, a severe depletion of cholinergic neurons(i.e., neurons that release acetylcholine, which is believed to be aneurotransmitter involved in learning and memory mechanisms). See,Jones, et al., Intern. J. Neurosci. 50:147 (1990); Perry, Br. Med. Bull.42:63 (1986); and Sitaram, et al., Science 201:274 (1978). It has beenobserved that nicotinic acetylcholine receptors, which bind nicotine andother nicotinic agonists with high affinity, are depleted during theprogression of SDAT. See, Giacobini, J. Neurosci. Res. 27:548 (1990);and Baron, Neurology 36:1490 (1986). As such, it would seem desirable toprovide therapeutic compounds which either directly activate nicotinicreceptors in place of acetylcholine or act to minimize the loss of thosenicotinic receptors.

Certain attempts have been made to treat SDAT. For example, nicotine hasbeen suggested to possess an ability to activate nicotinic cholinergicreceptors upon acute administration, and to elicit an increase in thenumber of such receptors upon chronic administration to animals. See,Rowell, Adv. Behav. Biol. 31:191 (1987); and Marks, J. Pharmacol. Exp.Ther. 226:817 (1983). It also has been proposed that nicotine can actdirectly to elicit the release of acetylcholine in brain tissue, toimprove cognitive functions, and to enhance attention. See, Rowell, etal., J. Neurochem. 43:1593 (1984); Sherwood, Human Psychopharm. 8:155(1993); Hodges, et al., Bio. of Nic. Edit. by Lippiello, et al., p. 157(1991); Sahakian, et al., Br. J. Psych. 154:797 (1989); and U.S. Pat.No. 4,965,074 to Leeson and U.S. Pat. No. 5,242,935 to Lippiello et al.Other methods for treating SDAT have been proposed, including U.S. Pat.No. 5,212,188 to Caldwell et al. and U.S. Pat. No. 5,227,391 to Caldwellet al., European Patent Application No. 588,917 and PCT WO 96/30372.Another proposed treatment for SDAT is COGNEX®, which is a capsulecontaining tacrine hydrochloride, available from Parke-Davis Division ofWarner-Lambert Company, which reportedly preserves existingacetylcholine levels in patients treated therewith.

Parkinson's disease (PD) is a debilitating neurodegenerative disease,presently of unknown etiology, characterized by tremors and muscularrigidity. A feature of the disease appears to involve the degenerationof dopaminergic neurons (i.e., which secrete dopamine). One symptom ofthe disease has been observed to be a concomitant loss of nicotinicreceptors which are associated with such dopaminergic neurons, and whichare believed to modulate the process of dopamine secretion. See, Rinne,et al., Brain Res. 54:167 (1991) and Clark, et al., Br. J. Pharm. 85:827(1985). It also has been proposed that nicotine can ameliorate thesymptoms of PD. See, Smith et al., Rev. Neurosci. 3(1):25 (1992).

Certain attempts have been made to treat PD. One proposed treatment forPD is SINEMET CR®, which is a sustained-release tablet containing amixture of carbidopa and levodopa, available from The DuPont MerckPharmaceutical Co. Another proposed treatment for PD is ELDEPRYL®, whichis a tablet containing selefiline hydrochloride, available from SomersetPharmaceuticals, Inc. Another proposed treatment for PD is PARLODEL®,which is a tablet containing bromocriptine mesylate, available fromSandoz Pharmaceuticals Corporation. Another method for treating PD and avariety of other neurodegenerative diseases has been proposed in U.S.Pat. No. 5,210,076 to Berliner et al.

Tourette's syndrome (TS) is an autosomal dominant neuropsychiatricdisorder characterized by a range of neurological and behavioralsymptoms. Typical symptoms include (i) the onset of the disorder beforethe age of 21 years, (ii) multiple motor and phonic tics although notnecessarily concurrently, (iii) variance in the clinical phenomenologyof the tics, and (iv) occurrence of quasi daily tics throughout a periodof time exceeding a year. Motor tics generally include eye blinking,head jerking, shoulder shrugging and facial grimacing; while phonic orvocal tics include throat clearing, sniffling, yelping, tongue clickingand uttering words out of context. The pathophysiology of TS presentlyis unknown, however it is believed that neurotransmission dysfunction isimplicated with the disorder. See, Calderon-Gonzalez et al., Intern.Pediat. 8(2):176 (1993) and Oxford Textbook of Medicine, Eds. Weatherallet al., Chapter 21.218 (1987).

It has been proposed that nicotine pharmacology is beneficial insuppressing the symptoms associated with TS. See, Devor et al., TheLancet 8670:1046 (1989); Jarvik, British J. of Addiction 86:571 (1991);McConville et al., Am. J. Psychiatry 148(6):793 (1991); Newhouse et al.,Brit. J. Addic. 86:521 (1991); McConville et al., Biol. Psychiatry31:832 (1992); and Sanberg et al., Proceedings from Intl. Symp. Nic. S39(1994). It also has been proposed to treat TS using HALDOL®, which ishaloperidol available from McNeil Pharmaceutical; CATAPRES®, which isclonidine available from Boehringer Ingelheim Pharmaceuticals, Inc.,ORAP®, which is pimozide available from Gate Pharmaceuticals; PROLIXIN®,which is fluphenazine available from Apothecon Division of Bristol-MyersSquibb Co.; and KLONOPIN®, which is clonazepam available fromHoffmann-LaRoche Inc.

Attention deficit disorder (ADD) is a disorder which affects mainlychildren, although ADD can affect adolescents and adults. See, Vinson,Arch. Fam. Med. 3(5):445 (1994); Hechtman, J. Psychiatry Neurosci.19(3):193 (1994); Faraone et al., Biol. Psychiatry 35(6):398 (1994) andMalone et al., J. Child Neurol. 9(2):181 (1994). Subjects suffering fromthe disorder typically have difficulty concentrating, listening,learning and completing tasks; and are restless, fidgety, impulsive andeasily distracted. Attention deficit disorder with hyperactivity (ADHD)includes the symptoms of ADD as well as a high level of activity (e.g.,restlessness and movement). Attempts to treat ADD have involvedadministration of DEXEDRINE®, which is a sustained release capsulecontaining dextroamphetamine sulfate, available from SmithKline BeechamPharmaceuticals; RITALIN®, which is a tablet containing methylphenidatehydrochloride, available from Ciba Pharmaceutical Company; and CYLERT®,which is a tablet containing premoline, available from AbbottLaboratories. In addition, it has been reported that administration ofnicotine to an individual improves that individual's selective andsustained attention. See, Warburton et al., Cholinergive Control ofCognitive Resources, Europsychobiology, Eds. Mendlewicz, et al., pp.43-46 (1993) and Levin et al. Psychopharmacology 123:55-63 (1996).

Schizophrenia is characterized by psychotic symptoms includingdelusions, catatonic behavior and prominent hallucinations, andultimately results in a profound decline in the psychosocial affect ofthe subject suffering therefrom. Traditionally, schizophrenia has beentreated with KLONOPIN®, which is available as a tablet containingclonezepam, available from Hoffmann-LaRoche Inc.; THORAZINE®, which isavailable as a tablet containing chlorpromazine, available fromSmithKline Beecham Pharmaceuticals; and CLORAZIL®, which is a tabletcontaining clozapine, available from Sandoz Pharmaceuticals. Suchneuroleptics are believed to be effective as a result of interactionthereof with the dopaminergic pathways of the CNS. In addition, adopaminergic dysfunction possessed by individuals suffering fromschizophrenia has been proposed. See, Lieberman et al., Schizophr. Bull.19:371 (1993) and Glassman, Amer. J. Psychiatry 150:546 (1993). Nicotinehas been proposed as being effective in effecting neurotransmitterdysfunction associated with schizophrenia. See, Merriam et al.,Psychiatr. Annals 23:171 (1993) and Adler et al., Biol. Psychiatry32;607 (1992). See also Freedman et al., Proc. Natl. Acad. Sci.94:587-592 (1997).

It would be desirable to provide a useful method for the prevention andtreatment of a disorder by administering a nicotinic compound to apatient susceptible to or suffering from such a disorder. It would behighly beneficial to provide individuals suffering from certaindisorders (e.g., CNS diseases) with interruption of the symptoms ofthose disorders by the administration of a pharmaceutical compositioncontaining an active ingredient having nicotinic pharmacology and whichhas a beneficial effect (e.g., upon the functioning of the CNS), butwhich does not provide any significant associated side effects (e.g.,increased heart rate and blood pressure attendant with interaction ofthat compound with cardiovascular sites). It would be highly desirableto provide a pharmaceutical composition incorporating a compound whichinteracts with nicotinic receptors, such as those which have thepotential to effect the functioning of the CNS, but which compound whenemployed in an amount sufficient to effect the functioning of the CNS,does not significantly effect those receptor subtypes which have thepotential to induce undesirable side effects (e.g., appreciable pressorcardiovascular effects and appreciable activity at skeletal musclesites).

SUMMARY OF THE INVENTION

The present invention relates to methods for the prevention or treatmentof disorders characterized by an alteration in normal neurotransmitterrelease, such as dopamine release. The present invention also relates tomethods for the prevention or treatment of disorders, such as centralnervous system (CNS) disorders, which are characterized by an alterationin normal neurotransmitter release. The methods involve administering toa subject an effective amount of an endo or exo form of a1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane, a1-aza-2-(3-pyridyl)bicyclo[2.2.2]octane, a1-aza-2-(3-pyridyl)bicyclo[3.2.2]nonane, a1-aza-7-(3-pyridyl)bicyclo[2.2.1]heptane, a1-aza-3-(3-pyridyl)bicyclo[3.2.2]nonane, or a1-aza-7-(3-pyridyl)bicyclo[3.2.2]nonane.

The present invention, in another aspect, related to a pharmaceuticalcomposition comprising an effective amount of a compound of the presentinvention. Such a pharmaceutical composition incorporates a compoundwhich, when employed in effective amounts, has the capability ofinteracting with relevant nicotinic receptor sites of a subject, andhence has the capability of acting as a therapeutic agent in theprevention or treatment of disorders characterized by an alteration innormal neurotransmitter release. Preferred pharmaceutical compositionscomprise novel compounds of the present invention.

The pharmaceutical compositions of the present invention are useful forthe prevention and treatment of disorders, such as CNS disorders, whichare characterized by an alteration in normal neurotransmitter release.The pharmaceutical compositions provide therapeutic benefit toindividuals suffering from such disorders and exhibiting clinicalmanifestations of such disorders in that the compounds within thosecompositions, when employed in effective amounts, have the potential to(i) exhibit nicotinic pharmacology and affect relevant nicotinicreceptors sites (e.g., act as a pharmacological agonist to activatenicotinic receptors), and (ii) elicit neurotransmitter secretion, andhence prevent and suppress the symptoms associated with those diseases.In addition, the compounds are expected to have the potential to (i)increase the number of nicotinic cholinergic receptors of the brain ofthe patient, (ii) exhibit neuroprotective effects and (iii) whenemployed in effective amounts do not cause appreciable adverse sideeffects (e.g., significant increases in blood pressure and heart rate,significant negative effects upon the gastro-intestinal tract, andsignificant effects upon skeletal muscle). The pharmaceuticalcompositions of the present invention are believed to be safe andeffective with regards to prevention and treatment of disorders, such asCNS disorders, which are characterized by an alteration in normalneurotransmitter release.

The foregoing and other aspects of the present invention are explainedin detail in the detailed description and examples set forth below.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds having the general formula I:

where A, A′, A″ and A′″ are individually substituent speciescharacterized as having a sigma m value greater than 0, often greaterthan 0.1, and generally greater than 0.2, and even greater than 0.3;less than 0, generally less than −0.1; or 0; as determined in accordancewith Hansch et al., Chem. Rev. 91:165 (1991); m, n and p areindividually 0, 1 or 2, and the sum of p plus m is equal to 1 or 2 whenn=0; R is a substituent other than hydrogen; j is an integer from 0 to5, preferably 0 or 1, and most preferably 0; and the wavy line in thestructure indicates that, depending upon the values of each of n, m, pand j, the compound can have the form of endo and exo isomers. The sumof m plus n plus p can vary, and typically is an integer from 1 to 4,with a sum of 1 to 3 being preferred. The identity of A, A′, A″ and A′″can vary, and each of those substituent species often has a sigma mvalue between about −0.3 and about 0.75, frequently between −0.25 andabout 0.6. More specifically, examples of A, A′, A″ and A′″ include H,F, Cl, Br, I, R′, NR′R″, CF₃, OH, CN, NO₂, C₂R′, SH, SCH₃, N₃, SO₂CH₃,OR′, SR′, C(═O)NR′R″, NR′C(-O)R′, C(═O)R′, C(═O)OR′, (CH₂)_(q)OR′,OC(═O)R′, OC(═O)NR′R″, and NR′C(═O) OR′, where R′ and R″ areindividually hydrogen or lower alkyl (e.g., C₁, -C₁₀ alkyl, preferablyC₁-C₆ alkyl, and more preferably methyl, ethyl, isopropyl or isobutyl),an aromatic group-containing species, and q is an integer from 1 to 6.In certain circumstances, it is preferred that the sigma m value of A″is not equal to 0. In addition, it is highly preferred that A ishydrogen, it is preferred that A′ is hydrogen, and normally A′″ ishydrogen. Generally, both A and A′ are hydrogen, and A′″ are allhydrogen; sometimes A and A′ are hydrogen, and A′″ is halo, OR′, OH,NR′R″, SH or SR′; and often A, A′ and A′″ are all hydrogen. For certainpreferred compounds, A″ is a non-hydrogen substitutent (i.e., suchcompounds are 5-substituted-3-pyridyl compounds). Typically, R is F, Cl,Br, I, R′ as defined hereinbefore, NO₂ or an aromatic group-containingspecies. R′ and R″ can be straight chain or branched alkyl, or R′ and R″can form a cycloalkyl functionality (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, quinuclidinyl).Representative aromatic group-containing species include pyrindinyl,quinolinyl, pyrimidinyl, phenyl, benzyl (where any of the foregoing canbe suitably substituted with at least one substitutent group, such asalkyl, halo, or amino substituents). Representative aromatic ringsystems are set forth in Gibson et al., J. Med. Chem. 39:4065 (1996).For NR′R′, the nitrogen and R′ and R″ can form a ring structure, such asaziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl ormorpholinyl. Typically, R is positioned at a carbon bridgehead of theazabicyclo moiety, at a carbon adjacent to the carbon or nitrogenbridgehead of the azabicyclo moiety, or at the carbon adjacent to thecarbon bearing the pyridyl substituent. The compounds represented ingeneral formula I are optically active.

A representative compound is a 1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane,which can have an endo or exo form, and for which n=0, m=1 and p=0. Arepresentative compound is a 1-aza-2-(3-pyridyl)bicyclo[2.2.2]octane,for which n-1, m=1 and p=0. A representative compound is a1-aza-2-(3-pyridyl)bicyclo[3.2.2]nonane, for which n=1, m=2 and p=0. Arepresentative compound is a 1-aza-7-(3-pyridyl)bicyclo[2.2.1]heptane,for which n=1, m=0 and p=0. A representative compond is a1-aza-3-(3-pyridyl)bicyclo[3.2.2]nonane, for which n=1, m=1 and p=1. Arepresentative compound is a 1-aza-7-(3-pyridyl)bicyclo[3.2.2]nonane,for which n=2, m=1 and p=0.

The manner in which certain 5-substituted-3-pyridyl compounds of thepresent invention can be synthetically produced can vary. For example,5-bromo-3-pyridyl containing compounds can be prepared using acombination of synthetic techniques known in the art. 5-bromosubstituted analogues of endo and exo1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane,1-aza-2-(3-pyridyl)bicyclo[2.2.2]octane, a1-aza-2-(3-pyridyl)bicyclo[3.2.2]nonane,1-aza-7-(3-pyridyl)bicyclo[2.2.1]heptane,1-aza-3-(3-pyridyl)bicyclo[3.2.2]nonane, or1-aza-7-(3-pyridyl)bicyclo[3.2.2]nonane can all be prepared startingfrom 5-bromonicotinic acid, which is commercially available from AldrichChemical Co. The 5-bromonicotinic acid is converted to the mixedanhydride with ethyl chloroformate and reduced with lithium aluminumhydride/tetrahydro furan (THF) at −78° C., to afford5-bromo-3-hydroxymethylpyridine, as reported by Ashimori et al., Chem.Pharm. Bull. 38:2446 (1990). Alternatively, the 5-bromonicotinic acid isesterified in the presence of sulfuric acid and ethanol, and theintermediate ester is reduced with sodium borohydride to yield5-bromo-3-hydroxymethylpyridine, according to the techniques reported inC. F. Natatis, et al., Org. Prep. and Proc. Int. 24:143 (1992). Theresulting 5-bromo-3-hydroxymethylpyridine can then be converted to the5-bromo-3-aminomethylpyridine utilizing a modification of the techniquesof O. Mitsunobu, Synthesis 1 (1981), or via treatment of5-bromo-3-hydroxymethylpyridine with thionyl chloride and reaction ofthe resulting 5-bromo-3-chloromethylpyridine with aqueousammonia/ethanol, according to North et al., WO 95/28400.5-Bromo-3-aminomethylpyridine can be converted to5-(1-azabicyclo[2.2.2]oct-2-yl)-3-(bromo)pyridine using methodsdescribed in U.S. Pat. No. 5,510,355 to Bencherif et al., thedisclosures of which are hereby incorporated by reference in itsentirety.

The manner in which the 5-bromo-3-pyridyl analogues of exo- and endo1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane and1-aza-7-(3-pyridyl)bicylo[2.2.1]heptane of the present invention can besynthetically prepared is analogous to the synthesis of thecorresponding unsubstituted parent compounds (see, U.S. Pat. No.5,510,355 to Bencherif et al.), except that5-bromo-3-aminomethylpyridine is utilized instead of3-aminomethylpyridine, in the formation of the Schiff base from thereaction with benzophenone. Thereafter, the 5-bromo Schiff base issubjected to the same procedures as described for the preparation of theunsubstituted parent compounds.

The manner in which 1-aza-3-(3-pyridyl)bicyclo[3.2.2]nonane and its5-bromo-3-pyridyl analogue can be prepared is analogous to the synthesisof 1-aza-2-(3-pyridyl)bicyclo[2.2.2]octane and its 5-bromo-3-pyridylanalogue. The ethyl ester of the appropriate 3-pyridyl acetic acid isreacted with 4-mesyloxymethylpyran (or 4-chloromethylpyran, or4-bromomethylpyran, or even 4-iodomethylpyran) in the presence oflithium diisopropyl amide (LDA), and the resulting2-(3-pyridyl)-2-(4-pyranomethyl)-acetic acid ethyl ester converted tothe corresponding carboxamide by treatment with ethanolicamino-1-(4-pyranomethyl)-2-(3-pyridyl)-ethane. This product is thensubjected to the same procedures as described in U.S. Pat. No. 5,510,355to Bencherif et al., for the synthesis of1-aza-2-(3-pyridyl)bicyclo[2.2.2]octane.

The manner in which 1-aza-7-(3-pyridyl)bicyclo[3.2.2]nonane and its5-bromo analogue can be prepared is analogous to the synthesis of2-3-pyridyl)-1-azabicyclo[2.2.2]octane and its 5-bromo analogue, exceptthat after the appropriate 3-aminomethylpyridine is converted to theSchiff base via reaction with benzophenone, the product is reacted with4-(mesyloxymethyl)-oxepane [or 4-(chloromethyl)-oxepane, or4-(bromomethyl)-oxepane, or even 4-(iodomethyl)-oxepane] in the presenceof LDA, and thereafter, the product of this reaction is subjected to thesame procedures as described in U.S. Pat. No. 5,510,355 to Bencherif etal., for the synthesis of 2-(3-pyridyl)-1-azabicyclo[2.2.2]octane.

The manner in which 1-aza-2-(3-pyridyl)bicyclo[3.2.2]nonane and its5-bromo-3-pyridyl analogue can be prepared is analogous to the synthesisof 1-aza-2-(3-pyridyl)bicyclo[2.2.2]octane and its 5-bromo-3-pyridylanalogue, except that after the appropriate 3-aminomethylpyridine isconverted to the Schiff base via reaction with benzophenone, the productis reacted with 4-mesyloxyethylpyran (or 4-chloroethylpyran, or4-bromoethylpyran, or even 4-iodoethylpyran) in the presence of LDA, andthereafter, the product of this reaction is subjected to the sameprocedures as described in U.S. Pat. No. 5,510,355 to Bencherif et al.,for the synthesis of 1-aza-3-(3-pyridyl)bicyclo [2.2.2]octane.

A representative synthetic technique for producing1-aza-2-(3-pyridyl)bicyclo[3.2.2]nonane is as follows:

A solution of diisopropyl amine (1.05 ml, 10.39 mmol) in dry THF(25 ml)was added to n-butyllithium (6.4 ml, 1.6 M solution in THF) at 0° C.;this mixture is then added to a stirred suspension of the Schiff baseobtained from the reaction of isopropylamine with 3-acetylpyridine [DeKimpe et al., Tetrahedron Lett., 34, 4693-4696, 1993 ] (1 g, 6.1 mmol)in dry THF (20 ml) at 0° C. LDA is added to the mixture through acannula, and the reaction is stirred for 45 mins at 0° C.Tetrahydropyran-4-methanyl bromide [Alfred Burger., J. Am. Chem. Soc.,72, 5512-5214] (1.21 g, 6.79 mmol) in dry THF at 0° C. is added tolithiated Schiff base. The reaction mixture is allowed to warm toambient temperature, followed by additional stirring for 12 hrs. Thereaction mixture is quenched with dilute hydrochloric acid (10%, 20 ml)and extracted with chloroform (3×40 ml). The combined organic extractsare dried over anhydrous potassium carbonate. Removal of solvent on arotary evaporator and purification by silica gel column chromatographyfurnishes 3-(4-oxanyl)-1-(3-pyridyl)-propan-1-one as a pale yellowcolored syrup. (1.14 g, 85%). To a stirred solution of 3-(4-oxanyl)-1-(3-pyridyl)-propan-1-one (600 mg, 2.73 mmol) in saturated sodiumbicarbonate solution (20 mL) is added hydroxylamine hydrochloride (1.87g, 27.3 mmol). The reaction mixture is stirred at ambient temperaturefor 10 hrs. The reaction mixture is extracted with chlroform (4×25mL),and the chloroform extracts dried over anhydrous potassium carbonate.Removal of solvent on a rotary evaporator yields a mixture of the Z andE isomers of 1-(hydroxyimino)-3-(4-oxanyl)-1-(3-pyridyl)-propane as athick, light brown colored syrup, which solidifies on standing (577 mg,90.1%). To a stirred suspension of1-(hydroxyimino)-3-(4-oxanyl)-1-(3-pyridyl)-propane (500 mg, 2.14 mmol)in ethanol (9520 mL), is added acetic acid (8 mL) at ambient temperatureover a period of 15 minutes. Zinc dust (6 g) is added to thissuspension, and the mixture refluxed for 4 h. The reaction mixture iscooled to room temperature and filtered through a celite pad. Thefiltrate is concentrated on a rotary evaporator to afford a white solid,which is dissolved in aqueous sodium hydroxide (50%, 10 mL). Theresulting aqueous solution is extracted with chloroform (6×25 mL), andthe combined extracts are dried over anhydrous potassium carbonate.Removal of solvent on a rotary evaporator furnishes3-(4-oxanyl)-1-(3-pyridyl)-propylamine as thick colorless liquid (440mg, 88.2%). 3-(4-Oxanyl)-1-(3-pyridyl)-propylamine (400 mg, 1.82 mmol)is dissolved in aqueous hydrobromic acid (48%, 10 mL) and the solutionis carefully transferred to a sealed glass tube. The mixture is thensaturated with HBr by bubbling HBr gas through the solution. The tube isthen sealed and heated at 120° C. for 10 hrs. The reaction mixture iscooled to ambient temperature, and the residual HBr is removed on arotary evaporator to afford a brown solid. The solid is dissolved inabsolute ethyl alcohol (250 mL), anhydrous potassium carbonate (4 g) isadded, and the mixture is refluxed for 10 h. The reaction mixture isthen filtered through a celite pad and the filtrate is concentrated. Thecrude product thus obtained is purified by column chromatography onsilica gel, using chloroform:methanol (9:1) as eluting solvent, toafford 1-aza-2-(3-pyridyl)bicyclo[3.2.2]nonane (258 mg, 70.25%) as alight tan oil. The free base is converted to the dihydrochloride, whichis obtained as an off-white crystalline solid.

A number of analogues substituted at C-5 of the pyridine ring in theaforementioned compounds can be prepared from the corresponding 5-bromocompound. For example, 5-amino substituted compounds and 5-alkylaminosubstituted compounds can be prepared from the corresponding 5-bromocompound using the general techniques described in C. Zwart, et al.,Recueil Trav. Chim. Pays-Bas 74:1062 (1955). 5-Alkoxy substitutedanalogues can be prepared from the corresponding 5-bromo compound usingthe general techniques described in D. L. Comins, et al., J. Org. Chem.55:69 (1990) and H. J. Den Hertog et al., Recl. Trav. Chim. Pays-Bas74:1171 (1955). 5-Ethynyl-substituted compounds can be prepared from theappropriate 5-bromo compound using the general techniques described inN. D. P. Cosford et al., J. Med. Chem. 39:3235 (1996). The 5-ethynylanalogues can be converted into the corresponding 5-ethenyl, andsubsequently the corresponding 5-ethyl analogues by successive catalytichydrogenation reactions using techniques known to those skilled in theart of organic synthesis. 5-Azido substituted analogues can be preparedfrom the corresponding 5-bromo compound by reaction with sodium azide indimethylformamide using techniques known in the art of organicsynthesis. 5-Alkylthio substituted analogues can be prepared from thecorresponding 5-bromo compound by reaction with an appropriatealkylmercaptan in the presence of sodium using techniques known to thoseskilled in the art of organic synthesis.

A number of 5-substituted analogues of the aforementioned compounds canbe synthesized from the corresponding 5-amino compounds via the5-diazonium intermediate. Among the other 5-substituted analogues thatcan be produced from 5-diazonium intermediates are: 5-hydroxy analogues,5-fluoro analogues, 5-chloro analogues, 5-bromo analogues, 5-iodoanalogues, 5-cyano analogues, and 5-mercapto analogues. These compoundscan be synthesized using the general techniques set forth in Zwart etal., supra. For example, 5-hydroxy substituted analogues can be preparedfrom the reaction of the corresponding 5-diazonium intermediate withwater. 5-Fluoro substituted analogues can be prepared from the reactionof the 5-diazonium intermediate with fluoroboric acid. 5-Chlorosubstituted analogues can be prepared from the reaction of the 5-aminocompound with sodium nitrite and hydrochloric acid in the presence ofcopper chloride. 5-Cyano substituted analogues can be prepared from thereaction of the corresponding 5-diazonium intermediate with potassiumcopper cyanide. 5-Amino substituted analogues can also be converted tothe corresponding 5-nitro analogue by reaction with fuming sulfuric acidand peroxide, according to the general techniques described in Y.Morisawa, J. Med. Chem. 20:129 (1977) for converting an aminopyridine toa nitropyridine. Appropriate 5-diazonium intermediates can also be usedfor the synthesis of mercapto substituted analogues using the generaltechniques described in J. M. Hoffman et al., J. Med. Chem. 36:953(1993). The 5-mercapto substituted analogues can in turn be converted tothe 5-alkylthio substituted analogues by reaction with sodium hydrideand an appropriate alkyl bromide using techniques known to those skilledin the art of organic synthesis. 5-Acylamido analogues of theaforementioned compounds can be prepared by reaction of thecorresponding 5-amino compounds with an appropriate acid anhydride oracid chloride using techniques known to those skilled in the art oforganic synthesis.

5-hydroxy substituted analogues of the aforementioned compounds can beused to prepare corresponding 5-alkanoyloxy substituted compounds byreaction with the appropriate acid, acid chloride, or acid anhydride,using techniques known to those skilled in the art of organic synthesis.

5-cyano substituted analogues of the aforementioned compounds can behydrolyzed using techniques known to those skilled in the art of organicsynthesis to afford the corresponding 5-carboxamido substitutedcompounds. Further hydrolysis results in formation of the corresponding5-carboxylic acid substituted analogues. Reduction of the 5-cyanosubstituted analogues with lithium aluminum hydride yields thecorresponding 5-aminomethyl analogue.

5-acyl substituted analogues can be prepared from corresponding5-carboxylic acid substituted analogues by reaction with an appropriatealkyl lithium using techniques known to those skilled in the art.

5-carboxylic acid substituted analogues of the aforementioned compoundscan be converted to the corresponding ester by reaction with anappropriate alcohol, according to methods known in the art of organicsynthesis. Compounds with an ester group at the 5-pyridyl position canbe reduced with sodium borohydride or lithium aluminum hydride usingtechniques known in the art of organic synthesis, to produce thecorresponding 5-hydroxymethyl substituted analogue. These analogues inturn can be converted to compounds bearing an ether moiety at the5-pyridyl position by reaction with sodium hydride and an appropriatealkyl halide, using conventional techniques. Alternatively, the5-hydroxymethyl substituted analogues can be reacted with tosyl chlorideto provide the corresponding 5-tosyloxymethyl analogue. The 5-carboxylicacid substituted analogues can also be converted to the corresponding5-alkylaminoacyl analogue by reaction with an appropriate alkylamine andthionyl chloride, using techniques known to those skilled in the art.5-Acyl substituted analogues of the aforementioned compounds can beprepared from the reaction of the appropriate 5-carboxylic acidsubstituted compound with an appropriate alkyl lithium salt, usingtechniques known to those skilled in the art of organic synthesis.

5-tosyloxymethyl substituted analogues of the aforementioned compoundscan be converted to the corresponding 5-methyl substituted compounds byreduction with lithium aluminum hydride, using techniques known to thoseskilled in the art of organic synthesis. 5-Tosyloxymethyl substitutedanalogues of the aforementioned compounds can also be used to produce5-alkyl substituted compounds via reaction with an alkyl lithium saltusing techniques known to those skilled in the art of organic synthesis.

5-hydroxy substituted analogues of the aforementioned compounds can beused to prepare 5-N-alkylcarbamoyloxy substituted compounds by reactionwith N-alkylisocyanates using techniques known to those skilled in theart of organic synthesis. 5-Amino substituted analogues of theaforementioned compounds can be used to prepare 5-N-alkoxycarboxamidosubstituted compounds by reaction with alkyl chloroformate esters, usingtechniques known to those skilled in the art of organic synthesis.

Analogous chemistries to the ones described hereinbefore for thepreparation of the 5-substituted analogues of the azabicyclo analoguescan be devised for the synthesis of 2-,4-, and 6-substituted analogues,utilizing the appropriate 2-, 4-, or 6-aminopyrdyl intermediate,followed by diazotization to the corresponding diazonium salt, and thenutilizing the same procedures for introducing the variety ofsubstituents into the pyridine ring as was described for the5-substituted analogues above. Similarly, by utilizing 2, 4 or6-bromopyridyl derivatives of the above azabicyclo analogues, andsubjecting each of these derivatives to the same procedures as describedfor introducing 5-substituents into the pyridyl ring from appropriate5-bromo precursors of these azabicyclo analogues, additional 2-, 4- or6-substituents can be obtained in the manner described above.

Chiral auxiliary reagents that have been reported in the literature canbe utilized in the synthesis of the pure enantiomers of theaforementioned exo and endo forms of 1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane, 1-aza-2-(3-pyridyl)bicyclo[2.2.2]octane,1-aza-2-(3-pyridyl)bicyclo[3.2.2]nonane,1-aza-7-(3-pyridyl)bicyclo[2.2.1]heptane,1-aza-7-(3-pyridyl)bicyclo[3,2,2]nonane, or1-aza-3-(3-pyridyl)bicyclo[3.2.2]nonane, D. Enders and U. Reinhold,Liebigs Ann. 11 (1996); D. Enders and D. L. Whitehouse, Synthesis 622(1996)). One approach can be carried out using(+)-2-amino-3-phenylethanol (or its (−)-enantiomer), which is reactedwith an appropriately substituted 3-pyridine carboxaldehyde in thepresence of an optically pure amino acid as a chiral auxiliary agent,followed by treatment with the required pyrano magnesium bromide reagentand N-deprotection (via hydrogenolysis), to afford the chirally purepyrano precursors of the aforementioned azabicyclo compounds. A secondalternative method is the use of the chiral auxiliary agent,(S)-1-amino-2-methyloxymethylpyrrolidine (SAMP) or(S)-1-amino-2-(1-methoxy-1-methylethyl)-pyrrolidine (SADP), or theirrespective R-isomers, by reaction with an appropriately substituted3-pyridine carboxaldehyde to form the corresponding oxime. Treatment ofthe oxime with the required pyrano magnesium bromide, followed bydeprotection with sodium/liquid ammonia will afford the appropriatechirally pure pyrano precursor of the aforementioned azabicyclocompounds. A third alternative method is the use of (+) or(−)-a-pinanone in place of benzophenone in the formation of theappropriate precursor Schiff base used in the synthesis of theaforementioned azabicyclo compounds. See, U.S. Pat. No. 5,510,355 toBencherif et al. For example, (+)-a-pinanone is reacted with anappropriately substituted 3-aminomethylpyridine to form thecorresponding Schiff base, which is then utilized in place of thecorresponding N-diphenylmethylidene-3-aminomethylpyridine, by reactionwith the requisite halo or mesyl pyrano intermediate in the presence ofLDA, followed by N-deprotection in NH₂OH/acetic acid, to afford theappropriate chirally pure pyrano precursor of the aforementionedazabicyclo compounds.

In the case of the exo- and endo1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptanes, use of the aboveenantioselective synthetic procedures will generate isomers with definedstereochemistry at C-2 and C-4 of the 1-azabicyclo[2.2.1]heptane ring;for example, one optical form of the chiral auxilliary agent that isutilized will afford chromatographically separable 2R,4S- and 2R,4R-exo- and endo-isomers of 1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptanes whilethe other optical isomer of the chiral auxilliary agent will afford thechromatographically separable 2S,4R- and 2S,4S-exo- and endo-isomers of1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptanes.

The present invention relates to methods of effecting the release ofneurotransmitters, such as dopamine, and to methods for providing theprevention of disorders characterized by an alteration of normalneurotransmitter release, such as dopamine release, in a subjectsusceptible to such a disorder, and for providing treatment to a subjectsuffering from a disorder. In particular, the method comprisesadministering to a patient an amount of a compound effective forproviding some degree of prevention of the progression of a disordersuch as a CNS disorder (i.e., provide protective effects), ameliorationof the symptoms of the disorder, and/or amelioration of the reoccurrenceof the disorder. In particular, the methods of the present inventioncomprise administering to a patient in need thereof, an amount of acompound selected from the group of compounds of general formula Ihereinabove, which amount is effective to prevent or treat the disorderaffecting the patient. The present invention further relates topharmaceutical compositions incorporating the compounds of generalformula I above. The compounds can be employed as racemic mixtures or asenantiomers.

The compounds can be employed in a free base form or in a salt form(e.g., as pharmaceutically acceptable salts). Examples of suitablepharmaceutically acceptable salts include inorganic acid addition saltssuch as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate;organic acid addition salts such as acetate, propionate, succinate,lactate, glycolate, malate, tartrate, citrate, maleate, fumarate,methanesulfonate, salicylate, p-toluenesulfonate, and ascorbate; saltswith acidic amino acids such as aspartate and glutamate; alkali metalsalts such as sodium salt and potassium salt; alkaline earth metal saltssuch as magnesium salt and calcium salt; ammonium salt; organic basicsalts such as trimethylamine salt, triethylamine salt, pyridine salt,picoline salt, dicyclohexylamine salt, and N,N-dibenzylethylenediaminesalt; and salts with basic amino acids such as the lysine salt andarginine salts. The salts may be in some cases be hydrates or ethanolsolvates.

A variety of conditions and disorders can be treated in accordance withthe present invention. See, for example, PCT WO 94/08992 and PCT WO96/31475, and U.S. Pat. No. 5,583,140 to Bencherif et al., U.S. Pat. No.5,597,919 to Dull et al. and U.S. Pat. No. 5,604,231 to Smith et al.Central nervous systems disorders which can be treated in accordancewith the methods of the present invention include CNS disordersassociated with the alteration of normal neurotransmitter release, suchas dopamine, in the brain, including conditions such as Parkinsonism,Parkinson's Disease, Tourette's Syndrome, attention deficit disorder,schizophrenia, and senile dementia of the Alzheimer's type.

The pharmaceutical compositions of the present invention can alsoinclude various other components as additives or adjuncts. Exemplarypharmaceutically acceptable components or adjuncts which are employed inrelevant circumstances include antioxidants, free radical scavengingagents, peptides, growth factors, antibiotics, bacteriostatic agents,immunosuppressives, buffering agents, anti-inflammatory agents,anti-pyretics, time release binders, anaesthetics, steroids andcorticosteroids. Such components can provide additional therapeuticbenefit, act to affect the therapeutic action of the pharmaceuticalcomposition, or act towards preventing any potential side effects whichmay be posed as a result of administration of the pharmaceuticalcomposition. In certain circumstances, a compound of the presentinvention can be employed as part of a pharmaceutical composition withother compounds intended to prevent or treat a particular disorder.

The manner in which the compounds are administered can vary. Thecompounds can be administered by inhalation (e.g., in the form of anaerosol either nasally or using delivery articles of the type set forthin U.S. Pat. No. 4,922,901 to Brooks et al.); topically (e.g., in lotionform); orally (e.g., in liquid form within a solvent such as an aqueousor non-aqueous liquid, or within a solid carrier); intravenously (e.g.,within a dextrose or saline solution); as an infusion or injection(e.g., as a suspension or as an emulsion in a pharmaceuticallyacceptable liquid or mixture of liquids); or transdermally (e.g., usinga transdermal patch). Although it is possible to administer thecompounds in the form of a bulk active chemical, it is preferred topresent each compound in the form of a pharmaceutical composition orformulation for efficient and effective administration. Exemplarymethods for administering such compounds will be apparent to the skilledartisan. For example, the compounds can be administered in the form of atablet, a hard gelatin capsule or as a time release capsule. As anotherexample, the compounds can be delivered transdermally using the types ofpatch technologies available from Novartis and Alza Corporation. Theadministration of the pharmaceutical compositions of the presentinvention can be intermittent, or at a gradual, continuous, constant orcontrolled rate to a warm-blooded animal, (e.g., a mammal such as amouse, rat, cat, rabbit, dog, pig, cow, or monkey); but advantageouslyis preferably administered to a human being. In addition, the time ofday and the number of times per day that the pharmaceutical formulationis administered can vary. Administration preferably is such that theactive ingredients of the pharmaceutical formulation interact withreceptor sites within the body of the subject that effect thefunctioning of the CNS. More specifically, in treating a CNS disorderadministration preferably is such so as to optimize the effect uponthose relevant receptor subtypes which have an effect upon thefunctioning of the CNS, while minimizing the effects upon receptorsubtypes in muscle and ganglia. Other suitable methods for administeringthe compounds of the present invention are described in U.S. Pat. No.5,604,231 to Smith et al., the disclosure of which is incorporatedherein by reference in its entirety.

Compounds of the present invention bind to relevant receptors and, arevery potent (i.e., effect relevant receptor subtypes at lowconcentrations), and are very efficacious (i.e., significantly affectrelevant receptor subtypes by activating those receptor subtypes to ahigh degree). Concentrations, determined as the amount of compound pervolume of receptor-containing tissue, typically provide a measure of thedegree to which that compound binds to and affects relevant receptorsubtypes. The compounds of the present invention are selective in thatat relevant concentrations (i.e., low concentrations) those compoundsbind to, and have an affect upon, receptors associated with the releaseof neurotransmitters, e.g., dopamine, within the CNS.

The appropriate dose of the compound is that amount effective to preventoccurrence of the symptoms of the disorder or to treat some symptoms ofthe disorder from which the patient suffers. By “effective amount”,“therapeutic amount” or “effective dose” is meant that amount sufficientto elicit the desired pharmacological or therapeutic effects, thusresulting in effective prevention or treatment of the disorder. Thus,when treating a CNS disorder, an effective amount of compound is anamount sufficient to pass across the blood-brain barrier of the subject,to bind to relevant receptor sites in the brain of the subject, and toelicit neuropharmacological effects (e.g., elicit neurotransmittersecretion, thus resulting in effective prevention or treatment of thedisorder). Prevention of the disorder is manifested by delaying theonset of the symptoms of the disorder. Treatment of the disorder ismanifested by a decrease in the symptoms associated with the disorder oran amelioration of the reoccurrence of the symptoms of the disorder.

The effective dose can vary, depending upon factors such as thecondition of the patient, the severity of the symptoms of the disorder,and the manner in which the pharmaceutical composition is administered.For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount sufficient to activaterelevant receptors to effect neurotransmitter (e.g., dopamine) releasebut the amount should be insufficient to induce effects on skeletalmuscles and ganglia to any significant degree. The effective dose ofcompounds will of course differ from patient to patient but in generalincludes amounts starting where CNS effects or dopamine release arefirst observed in the patient being treated, but below the amount wheremuscular effects are observed.

Typically, the effective dose of compounds generally requiresadministering the compound in an amount of less than 1 ug/kg of patientweight. Often, the compounds of the present invention are administeredin an amount from 10 ng to less than 1 ug/kg of patient weight,frequently between about 0.1 ug to less than 1 ug/kg of patient weight,and preferably between about 0.1 ug to about 0.5 ug/kg of patientweight. Compounds of the present invention can be administered in anamount of 0.3 to 0.5 ug/kg of patient weight. For compounds of thepresent invention that do not induce effects on muscle or ganglion-typenicotinic receptors at low concentrations, the effective dose is lessthan 50 ug/kg of patient weight; and often such compounds areadministered in an amount from 0.5 ug to less than 50 ug/kg of patientweight. The foregoing effective doses typically represent that amountadministered as a single dose, or as one or more doses administered overa 24 hour period.

For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount of at least about 1,often at least about 10, and frequently at least about 25 ug/24hr./patient. For human patients, the effective dose of typical compoundsrequires administering the compound which generally does not exceedabout 500, often does not exceed about 400, and frequently does notexceed about 300 ug/24 hr./patient. In addition, administration of theeffective dose is such that the concentration of the compound within theplasma of the patient normally does not exceed 500 ng/ml, and frequentlydoes not exceed 100 ng/ml.

The compounds useful according to the method of the present inventionhave the ability to pass across the blood-brain barrier of the patient.As such, such compounds have the ability to enter the central nervoussystem of the patient. The log P values of typical compounds, which areuseful in carrying out the present invention are generally greater thanabout 0, often are greater than about 0.5, and frequently are greaterthan about 1.5. The log P values of such typical compounds generally areless than about 4, often are less than about 3.5, and frequently areless than about 3.0. Log P values provide a measure of the ability of acompound to pass across a diffusion barrier, such as a biologicalmembrane. See, Hansch, et al., J. Med. Chem. 11:1 (1968).

The compounds useful according to the method of the present inventionhave the ability to bind to, and in most circumstances, cause activationof, nicotinic dopaminergic receptors of the brain of the patient. Assuch, such compounds have the ability to express nicotinic pharmacology,and in particular, to act as nicotinic agonists. The receptor bindingconstants of typical compounds useful in carrying out the presentinvention generally exceed about 0.1 nM, often exceed about 1 nM, andfrequently exceed about 10 nM. The receptor binding constants of suchtypical compounds generally are less than about 1 M, often are less thanabout 100 nM, and frequently are less than about 2 nM. Receptor bindingconstants provide a measure of the ability of the compound to bind tohalf of the relevant receptor sites of certain brain cells of thepatient. See, Cheng, et al., Biochem. Pharmacol. 22:3099 (1973).

The compounds useful according to the method of the present inventionhave the ability to demonstrate a nicotinic function by effectivelyeliciting neurotransmitter secretion from nerve ending preparations(i.e., synaptosomes). As such, such compounds have the ability to causerelevant neurons to release or secrete acetylcholine, dopamine, andother neurotransmitters. Generally, typical compounds useful in carryingout the present invention provide for the secretion of dopamine inamounts of at least one third, typically at least about 10 times less,frequently at least about 100 times less, and sometimes at least about1,000 times less, than those required for activation of muscle organglion-type nicotinic receptors. Certain compounds of the presentinvention can provide secretion of dopamine in an amount which canexceed that elicited by an equal molar amount of (S)-(−)-nicotine.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, areselective to certain relevant nicotinic receptors, but do not causesignificant activation of receptors associated with undesirable sideeffects at concentrations at least 10 times higher than those requiredfor activation of dopamine release. By this is meant that a particulardose of compound resulting in prevention and/or treatment of a CNSdisorder, is essentially ineffective in eliciting activation of certainganglionic-type nicotinic receptors at concentration higher than 5times, preferably higher than 100 times, and more preferably higher than1,000 times, than those required for activation of dopamine release.This selectivity of certain compounds of the present invention againstthose receptors responsible for cardiovascular side effects isdemonstrated by a lack of the ability of those compounds to activatenicotinic function of adrenal chromaffin tissue at concentrations atleast 10 times greater than those required for activation of dopaminerelease.

Compounds of the present invention, when employed in effective amountsin accordance with the method of the present invention, are effectivetowards providing some degree of prevention of the progression of CNSdisorders, amelioration of the symptoms of CNS disorders, anamelioration to some degree of the reoccurrence of CNS disorders.However, such effective amounts of those compounds are not sufficient toelicit any appreciable side effects, as demonstrated by increasedeffects relating to the cardiovascular system, and effects to skeletalmuscle. As such, administration of certain compounds of the presentinvention provides a therapeutic window in which treatment of certainCNS disorders is provided, and side effects are avoided. That is, aneffective dose of a compound of the present invention is sufficient toprovide the desired effects upon the CNS, but is insufficient (i.e., isnot at a high enough level) to provide undesirable side effects.Preferably, effective administration of a compound of the presentinvention resulting in treatment of CNS disorders occurs uponadministration of less than ⅕, and often less than {fraction (1/10)}that amount sufficient to cause any side effects to a significantdegree.

The following examples are provided to further illustrate the presentinvention, and should not be construed as limiting thereof.

EXAMPLE 1

Sample No. 1 is (+/−)-1-aza-2-(3-pyridyl)bicyclo[2.2.2]octane which isprepared in accordance with the techniques set forth in U.S. Pat. No.5,559,124, the disclosure of which is incorporated herein by referencein its entirety.

EXAMPLE 2

Sample No. 2 is (+/−)-5-(1-azabicyclo[2.2.2]oct-2-yl)-3-bromo)pyridine,which is prepared in accordance with the following techniques.

Tetrahydropyranyl-4,4-diethylcarboxylate: Sodium (20.7 g, 900 mmol) wasdissolved in dry ethanol (300 ml); to this mixture was added diethylmalonate (144 g, 900 mmol) and 2,2-dichlorodiethylether (128.64 g, 900mmol). The reaction mixture was refluxed for 15 hours and cooled to roomtemperature. The solvent was removed on a rotary evaporator, the productacidified with 10% HCl (200 ml), extracted with ethyl acetate (4×200ml), and dried over anhydrous sodium sulfate. Removal of solvent on arotary evaporator, followed by distillation (170-175° C., 22 mm Hg)furnished the product (98.0 g, 48% yield).

Tetrahydropyranyl-4,4-dicarboxylic acid: To a stirred solution ofdiester tetrahydropyranyl4,4-diethylcarboxylate (40.00 g., 173 mmol) inethanol (100 ml) was added potassium hydroxide (21.43 g, 382 mmol) inethanol (300 ml). After the completion of the addition, the reactionmixture was stirred for 15 minutes at ambient temperature and thenrefluxed for 2.5 hours. Water (40 ml) was added to the thick, whitesuspension, and solvent was removed on a rotary evaporator. Water (40ml) was added to the remaining residue and the resulting mixture thenacidified with concentrated sulfuric acid (20 ml). The acidic solutionwas extracted with diethyl ether (3×300 ml), and the combined organiclayers were dried over anhydrous sodium sulfate. Removal of solvent on arotary evaporator yielded the product (27.3 g, 90.17% yield).

Tetrahydropyranyl-4-carboxylic acid: Tetrahydropyranyl-4,4-dicarboxylicacid was taken in a round bottom flask fitted with a reflux condenserand was gradually heated to 180° C. When evolution of carbon dioxidedecreased, the reaction was allowed to cool to room temperature. Themono acid thus obtained was purified by distillation (160-165° C. at 22mm Hg) to yield tetrahydropyranyl-4-carboxylic acid (16.1 g, 71.8%yield).

Tetrahydropyran-4-methanol: To a stirred solution of lithium aluminumhydride (13.99 g, 368 mmol) in dry tetrahydrofuran (50 ml) was added drytetrahydrofuran (50 ml), and tetrahydropyranyl-4-carboxylic acid (15.96g, 123 mmol). The reaction mixture was refluxed for 24 hours then cooledto 0° C., and a solution of sodium hydroxide (30%, 25 ml) was addeddrop-wise. The solid thus obtained was filtered off, and repeatedlywashed with tetrahydrofuran. The filtrate was dried over anhydroussodium carbonate. Removal of solvent followed by purification over asilica gel column furnished the pyranyl alcohol,tetrahydropyran-4-methanol (13.1 g, 91% yield).

Tetrahydropyranyl-4-methansulfonate ester: To a stirred solution oftetrahydropyranyl-4-methanol (13.0 g, 122 mmol), in dichloromethane (50ml) was added triethylamine (20.41 g, 201 mmol) in dichloromethane (100ml) followed by drop-wise addition of mesyl chloride (19.25 g, 168 mmol)at 0° C. and the reaction mixture was stirred for 1 hour at 0° C. andthen at room temperature for 14 hours. The reaction mixture was pouredinto a saturated solution of sodium bicarbonate (100 ml), extracted withdichloromethane (200 ml), dried over anhydrous sodium sulfate followedby removal of solvent on a rotary evaporator and purification oversilica gel column chromatography to afford tetrahydropyranyl-4-methanolmethanesulfonate ester (13.9 g, 63.8% yield).

3-Bromo-5-hydroxymethylpyridine: 3-Bromo-5-hydroxymethylpyridine can beprepared according to either of two techniques.

Method A: Ethyl 5-bromo-3-nicotinate is prepared by dissolving5-bromo-3-nicotinic acid (50 g, 247.5 mmol) in ethyl alcohol (130 ml) atroom temperature. To this solution was added drop-wise concentratedsulfuric acid (50 ml, 938 mmol) with constant stirring. After completionof the addition, the reaction mixture was refluxed for 40 hours andcooled to 0° C., followed by neutralization with saturated sodiumcarbonate solution (pH=8). The neutralized solution was extracted withchloroform (3×200 ml), and dried over anhydrous sodium sulfate. Removalof solvent on a rotary evaporator furnished ethyl 5-bromo-3-nicotinate(39.85 g, 97% yield).

Ethyl 5-bromo-3-nicotinate is reduced by adding sodium borohydride (29.6g., 782.6 mmol) to a stirred solution of ethyl 5-bromo-3-nicotinate (20g, 86.9 mmol) in ethyl alcohol (450 ml). The reaction mixture wasrefluxed for 30 hours, then the solvent was removed on a rotaryevaporator. The solid thus obtained was treated with 10% dilutehydrochloric acid (3N, 40 ml) to pH6, and the resulting aqueous solutionextracted with ethyl acetate (3×200 ml), and dried over nhydrous sodiumsulfate. Removal of solvent followed by purification over silica gelcolumn chromatography furnished 3-bromo-5-hydroxymethyl pyridine (8.5 g,52% yield).

Method B: To a suspension of 5-bromonicotinic acid (1 g, 4.9 mmol) inbenzene (20 ml) was added triethylamine (0.73 ml, 5.2 mmol) at roomtemperature. After stirring for 5 minutes, ethyl chloroformate (0.5 ml,5.2 mmol) was added, and the mixture was stirred for a further 1 hour atroom temperature. The triethylamine hydrochloride salt thusprecipitated, was filtered off, and the filtrate was evaporated todryness to give the mixed anhydride, which was not isolated, but takenup in dry tetrahydrofuran (26 ml), and the solution immediately added toa stirred suspension of lithium aluminum hydride (0.2 g, 5.29 mmol) indry tetrahydrofuran (7 ml) at −78° C. This mixture was stirred for 30min. at −78° C. Workup in the usual manner, followed by purificationover silica gel column chromatography yielded3-bromo-5-hydroxymethylpyridine (0.762 g, 82% yield).

5-Bromo-3-pyridinemethanamine: 5-Bromo-3-pyridinemethanamine can beprepared according to either of two techniques.

Method A: 5-Bromo-3-N-(phthalimidomethyl)-pyridine is produced by addingtriphenylphosphine (12.1 g, 46.3 mmol) and phthalimide (6.8 g, 46.3mmol) in dry tetrahydrofuran (70 ml) to a stirred suspension of3-bromo-5-hydroxymethylpyridine (6.7 g, 35.6 mmol), and then adding DEAD(7.3 ml, 46.3 mmol) in dry tetrahydrofuran (30 ml) drop-wise. Thereaction mixture was stirred at room temperature overnight. Afterremoval of the solvent on a rotary evaporator, the crude material waspurified by column chromatography over silica gel to yield the product(9.5 g, 85% yield).

5-Bromo-3-N-(phthalimidomethyl)-pyridine is (7 g, 25 mmol) thenhydrolyzed by treatment with aqueous methylamine (40%, 50 ml), andrefluxing the mixture for 3 hours. Solvent was removed on a rotaryevaporator to yield a pale-yellow colored solid, which was then taken upinto concentrated hydrochloric acid (50 ml) and the solution refluxedfor 15 hours. The reaction mixture was basified (pH =10-11) with aqueoussodium hydroxide (50%), extracted with chloroform (5×40 ml), and driedover anhydrous potassium carbonate. The solvent was removed on a rotaryevaporator and the product purified by column chromatography over silicagel to yield 5-bromo-3-pyridinemethanamine (2.8 g, 67.97% yield).

Method B: 3-Bromo-5-hydroxymethylpyridine (1.1 g, 5.8 mmol) was added tothionyl chloride (5 ml) at 0° C. under nitrogen over 5 minutes. Thesolution was stirred at room temperature for 1 hour, re-cooled to 0° C.,and dry ether (40 ml) was added. The resulting solid was filtered off,washed with ether and added to a stirred solution of ammonia (28%, 30ml) and ethyl alcohol (40 ml) at 0° C. The solution was then stirred atroom temperature for 20 hours. The solvent was removed on a rotaryevaporator, and the crude material partitioned between sodium hydroxide(2N, 30 ml) and dichloromethane (60 ml). The organic layer was driedover anhydrous sodium sulfate, the solvent removed and the residuepurified by flash chromatography over silica gel usingCHCl₃/ethanol/concentrated aqueous ammonia solution (100:6:1) as eluentto afford 5-bromo-3-pyridinemethanamine (785 mg, 72% yield).

5-Bromo-N-(diphenylmethylidene)-3-(aminomethyl)-pyridine: To a solutionof 5-bromo-3-pyridinemethanamine 10 (1.5 g, 8.02 mmol) in dry toluene (5ml), was added benzophenone (1.6 g, 8.79 mmol) and p-toluene sulfonicacid (PTSA, 2 mg). The reaction mixture was refluxed for 48 hours usinga Dean-Stark apparatus. After the completion of the reaction, thesolvent was removed in vacuum and the crude material was purifiedthrough silica gel column chromatography to yield5-bromo-N-(diphenylmethylidene)-3-(aminomethyl)-pyridine (1.9 g, 56%yield).

1-Amino-1-[3-(5-bromopyridyl)]-2-(4-tetrahydropyrano)-ethane: To asolution of diisopropyl amine (0.55 m., 3.92 mmol) in drytetrahydrofuran (3 ml) was added n-butyl lithium (2.45 ml, 1.6 Msolution in tetrahydrofuran) at 0° C.; this mixture was then added to astirred suspension of Schiff base,5-bromo-N-(diphenylmethylidene)-3-(aminomethyl)-pyridine (1.00 g, 3.01mmol) in dry tetrahydrofuran (10 ml) at −78° C., LDA (0.5 ml, 3.92 mmol)was added through a cannula, and the reaction mixture was stirred for 45minutes at 78° C. Tetrahydropyranyl-4-methanol methanesulfonate ester(0.706 g, 3.92 mmol) in dry tetrahydrofuran at −78° C. was then added tothe lithiated Schiff base. The reaction mixture was allowed to warm toambient temperature followed by additional stirring for 12 hours. Thereaction mixture was quenched with hydrochloric acid (10% w/v, 20 ml)and stirred for 30 minutes, followed by extraction with ethyl acetate(3×25 ml). The resulting aqueous solution was made basic (pH=8-9) byadding solid potassium carbonate, and the mixture extracted withchloroform (3×25 ml). The combined organic layers were dried overanhydrous potassium carbonate. Removal of solvent on a rotary evaporatorand purification of the residue by silica gel column chromatographyfurnished 1-amino-1-[3-(5-bromopyridyl)]-2-(4-tetrahydropyrano)-ethaneas a pale-yellow colored syrup which could not be distilled (600 mg, 70%yield).

(+/−)-5-(1-azabicyclo[2.2.2oct-2-yl)-3-(bromo)pyridine dihydrochloride:1-Amino-1-[3-(5-bromopyridyl)]-2-(4-tetrahydropyrano)-ethane (12) (500mg, 1.76 mmol) was dissolved in aqueous hydrobromic acid (48%, 10 ml)and hydrogen bromide gas was passed through the solution untilsaturated. The reaction mixture was then carefully transferred to apressure tube and heated at 120° C. for 16 hours. The reaction mixturewas allowed to cool to ambient temperature, and was then transferred toa round bottom flask. HBr was removed on a rotary evaporator. Theresulting dark brown residue was taken up into absolute ethanol and thesolution heated with potassium carbonate (3 g) for 12 hours. Thereaction mixture was cooled to room temperature and filtered through acelite pad. Removal of solvent followed by purification of the resultingresidue over silica gel column chromatography, yielded the product (150mg, 32% yield).

5-(1-azabicyclo[2.2.2]oct-2-yl-3-(bromo)pyridine free base (90 mg, 0.33mmol) was dissolved in ethanolic HCl (5 ml) and the mixture sonicatedfor 5 minutes. The solvent was removed on a rotary evaporator to yield asolid residue which was recrystallized from isopropanol to afford thedihydrochloride salt as a light brown crystalline solid (100 mg).

EXAMPLE 3

Sample No. 3 is exo 1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane, which isprepared according to the following techniques.

N-(diphenylmethylidene)-3-(aminomethyl)pyridine: Benzophenone (10.92 g,60 mmol), 3-(aminomethyl)pyridine (6.48 g, 60 mmol) andp-toluenesulfonic acid (10 mg) were dissolved in 30 mL benzene, and thereaction mixture was heated to reflux under a nitrogen atmosphere with aDean-Stark trap. The completion of the reaction (12-16 hours) wasdetermined after the calculated amount of water was collected in theDean-Stark trap. Benzene was removed on a rotary evaporator and theresulting Schiff base was used in the next step without furtherpurification.

Tetrahydro-3-furanmethanol methanesulfonate: Methanesulfonyl chloride(18 mmol, 1.39 mL) was added to a flask containing(±)-tetrahydro-3-furanmethanol (1.53 g, 15.0 mmol) in tetrahydrofuran(25 mL) and triethylamine (3.13 mL, 22.5 mmol) at 0° C. under a nitrogenatmosphere. The cooling bath was removed and the reaction mixture wasstirred overnight. A saturated solution of NaHCO₃ (15 mL) was added tothe reaction mixture followed by extraction with diethyl ether (3×15mL). The combined organic extracts were dried over anhydrous magnesiumsulfate. Filtration followed by concentration on a rotary evaporatoryielded the product as a pale yellow solid (2.13 g) which was used inthe next step without further purification.

1-Amino-1-(3-pyridyl)-2-(3-tetrahydrofuranyl)-ethane: LDA (14.66 mmol)was generated at 0° C. by adding n-BuLi (6.4 mL of 2.3 M solution inhexane, 14.66 mmol) to a solution of diisopropylamine (2.27 mL, 16.0mmol) in dry tetrahydrofuran (THF) (13 mL).N-(diphenylmethylidene)-3-(aminomethyl)pyridine (3.62 g, 13.33 mmol) wasdissolved in dry tetrahydrofuran (13 mL) and the solution cooled to −78°C. under a nitrogen atmosphere. LDA was then transferred to the solutionof N-(diphenylmethylidene)-3-(aminomethyl)pyridine using a double tippedneedle under a positive nitrogen atmosphere. The resulting purplesuspension was stirred for a further 45 minutes, during which time thetemperature of the reaction mixture was allowed to rise to −4° C.Tetrahydro-3-furanmethanol methanesulfonate (2.64 g, 14.7 mmol) intetrahydrofuran (10 mL) was then added via a syringe and the reactionmixture was allowed to warm to ambient temperature followed byadditional stirring for 12 hours. Hydrochloric acid (10% aq., 20 mL) wasadded, and the reaction mixture was stirred for 20-30 minutes followedby extraction with ethyl acetate (3×25 mL). The resulting aqueoussolution was first made basic by adding solid K₂CO₃, and then extractedwith chloroform (3×25 mL). The combined organic extracts were dried overanhydrous K₂CO₃. Filtration was followed by evaporation of chloroform toyield 1-amino-1-(3-pyridyl)-2-(3-tetrahydrofuranyl)-ethane as adiastereomeric (50:50) mixture (pale yellow oil, 2.03 g) which was usedin the next step without further purification.

Exo-1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane:1-Amino-1-(3-pyridyl)-2-(3-tetrahydrofuranyl)-ethane (960 mg, 5 mmol)was dissolved in hydrobromic acid (aq., 48%, 12 mL). Hydrogen bromidegas was generated according to the procedure described in Vogel'sTextbook of Practical Organic Chemistry, 5th ed., Longman Scientific &Technical, 1991, pp 437-438, by dropwise addition of bromine totetralene, and the HBr gas thus generated was passed through the acidicsolution of 1-amino-1-(3-pyridyl)-2-(3-tetrahydrofuranyl)-ethane untilsaturated. The solution was then carefully transferred to a pressuretube and heated at 100° C. under pressure for 12-16 hours. The tube wasallowed to cool to ambient temperature and the contents then transferedto a round bottom flask. The mixture was basified with solid K₂CO₃followed by stirring for 2 hours. The reaction mixture was thenextracted with chloroform (3×15 mL). The combined organic extracts weredried over anhydrous K₂CO₃. Filtration, followed by removal of solventon a rotary evaporator yielded 700 mg of product as a dark brown oil.Separation of the endo and exo isomers in the product was achieved bysilica gel column chromatography using 15% (v/v) methanol in chloroformas the eluting solvent. The fractions with R_(f) value 0.43 (onanalytical silica plates with 15% (v/v) methanol in chloroform as theeluting solvent) were concentrated on a rotary evaporator to obtainexo-1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane as a pale brown oil (190mg) which was distilled under vacuum (92-95° C.) at 0.0025 mm Hg) toobtain 115 mg (13.2%) of colorless oil.

EXAMPLE 4

Sample No. 4 is endo -1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane which isisolated as follows:

The fractions from Example 3 containing the endo isomer with an R_(f)value of 0.33 (on analytical silica plates with 15% (v/v) methanol inchloroform as the eluting solvent) were concentrated on a rotaryevaporator to afford endo-1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane as apale brown oil, which was distilled (101 to 104° C. at 0.0025 mm Hg) toobtain 80 mg of pure endo-1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane(9.1%) as a colorless oil.

EXAMPLE 5

Sample No. 5 is 1-aza-7-(3-pyridyl)bicyclo[2.2.1]heptane which wasprepared according to the following techniques.

1-Amino-1-(3-pyridyl)-1-(4-tetrahydropyranyl)-methane: The methaneaminederivative was synthesized essentially according to the proceduredescribed for the synthesis of1-amino-1-(3-pyridyl)-2-(3-tetrahydrofuranyl)-ethane. Thus,tetrahydropyran-4-ol methane sulfonate (0.99 g, 5.5 mmol), preparedaccording to the procedure of Suto et al., J. Med. Chem., 34:2484(1991), was treated with the imine anion generated by reactingN-(diphenylmethylidene)-3-(aminomethyl)pyridine (1.36 g, 5.0 mmol) withLDA (5.5 mmol in 5.0 mL tetrahydrofuran). A work up similar to the onedescribed for the synthesis of1-amino-1-(3-pyridyl)-2-(3-tetrahydrofuranyl)-ethane, followed bypurification by column chromatography (15% methanol in chloroform)yielded 1-amino-1-(3-pyridyl)-1-(4-tetrahydropyranyl)-methane (499 mg)in 52% yield.

1-aza-7-(3-pyridyl)bicyclof2.2.1.]heptane: Treatment of1-amino-1-(3-pyridyl)-1-(4-tetrahydropyranyl)-methaneamine (576 mg, 3mmol) with hydrobromic acid, as described for the synthesis of the1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptanes resulted in formation of theproduct, as a dark brown oil which was purified by column chromatography(15% methanol in chloroform), followed by distillation (90° C. at 0.005mm Hg) under reduced pressure to obtain the product as a colorless oil(260 mg, 51% from 1-amino-1-(3-pyridyl)-1-(4-tetrahydropyranyl)-methane.

EXAMPLE 6

Sample No. 6 is 5-(1-azabicyclo[2.2.2]oct-2-yl-3-(amino)pyridinetrihydrochloride, which is prepared in accordance with the followingtechniques.

5-(1-azabicyclo[2.2.2]oct-2-yl)-3-(bromo)pyridine (120 mg), was mixedwith aqueous ammonium hydroxide (20 mL, 28%) in a sealed tube, coppersulfate (200 mg) was added, and the reaction mixture was heated at 180°C. for 14 hours. The reaction mixture was allowed to cool to ambienttemperature and then extracted with chloroform (4×20 mL). The combinedorganic extracts were dried over anhydrous potassium carbonate,filtered, and the solvent removed on a rotary evaporator to afford adark syrup. This crude product was subjected to column chromatographyover silica gel using chloroform:methanol:triethylamine (9:1:1) to yieldan initial fraction of5-(1-azabicyclo[2.2.2]oct-2-yl)-3-(amino)pyridine, which after removalof solvent afforded a light brown solid (20 mg) homogeneous on TLC(silica, chloroform:methanol 95:5). An impure fraction was alsoobtained, which afforded a brown solid (40 mg), found to be mostly thedesired compound with minor impurities on TLC analysis (total yield^(˜)65%).

5-(1-azabicyclo[2.2.2]oct-2-yl)-3-(amino)pyridine free base (20 mg, 0.98mmol) was dissolved in ethanolic HCl (2 mL) and the mixture sonicatedfor 5 minutes. The solvent was removed on a rotary evaporator to yield aviscous oil, which solidified, to afford the trihydrochloride salt ofthe product as a brown colored solid (20 mg from ethanol/ether (9:1), mp210° C. with decomposition.

EXAMPLE 7

Sample No. 7 is 5-(1-azabicyclo[2.2.2]oct-2-yl)-3-(ethoxy)pyridinedihydrochloride, which is prepared according to the followingtechniques.

To a stirred solution of5-(1-azabicyclo[2.2.2]oct-2-yl)-3-(amino)pyridine trihydrochloride (25mg, 0.08 mmol) in dry ethanol (3 mL) was added isoamyl nitrite (0.1 mL,0.742 mmol) and the mixture was refluxed for 2 h. When TLC analysis ofthe reaction mixture showed absence of starting material, the heatingwas stopped and the mixture was allowed to cool to ambient temperature.The solvent then was removed on a rotary evaporator to yield a thickbrown oil, which solidified upon addition of dry diethyl ether. Theproduct thus obtained was dissolved in chloroform and kept overnight at4° C. to induce crystallization. The resulting solids were filtered,washed with diethyl ether and finally dried under vacuum for 24 h, toyield the product in the form of a dihydrochloride salt (10 mg, 51.4%)as colorless needles.

EXAMPLE 8

Sample No. 8 is 5-(1-azabicyclo[2.2.2]oct-2-yl-3-(isopropyloxy)pyridinedihydrochloride, which is prepared according to the followingtechniques.

To a stirred solution of5-(1-azabicyclo[2.2.2]oct-2-yl)-3-(amino)pyridine trihydrochloride (50mg, 0.16 mmol) in dry isopropanol (5 mL) was added isoamyl nitrite (0.1mL, 0.97 mmol) and the reaction mixture was refluxed for 2 h. When TLCanalysis of the reaction mixture showed the absence of startingmaterial, the heating was stopped, and the solvent was removed undervacuum. A white solid was obtained upon the addition of dry diethylether. The solid was dissolved with heating in a minimum amount ofchloroform, and the solution kept over night at 4° C. to inducecrystallization of the dihydrochloride salt. The compound thus obtainedwas filtered and dried under vacuum for 24 h, to afford thedihydrochloride salt of the product (28 mg, 55%) as colorless needles.

Comparison Example

For comparison purposes, Sample No. C-1 is (S)-(−)-nicotine, which hasbeen reported to have demonstrated a positive effect toward thetreatment of various CNS disorders.

EXAMPLE 9 Determination of Log P Value

Log P values, which have been used to assess the relative abilities ofcompounds to pass across the blood-brain barrier (Hansch, et al., J.Med. Chem. ii:1 (1968)), were calculated according using the Cerius²software package Version 3.0 by Molecular Simulations, Inc. Log P valuesare reported in Table 1 below.

EXAMPLE 10 Determination of Binding to Relevant Receptor Sites

Binding of the compounds to relevant receptor sites was determined inaccordance with the techniques described in U.S. Pat. No. 5,597,919 toDull et al. Inhibition constants (Ki values), reported in nM, werecalculated from the IC₅₀ values using the method of Cheng et al.,Biochem, Pharmacol. 22:3099 (1973). The results are reported in Table 1below.

EXAMPLE 11 Determination of Dopamine Release

Dopamine release was measured using the techniques described in U.S.Pat. No. 5,597,919 to Dull et al. Release is expressed as a percentageof release obtained with a concentration of (S)-(−)-nicotine resultingin maximal effects. Reported EC₅₀ values are expressed in nM, andE_(max) values represent the amount released relative to(S)-(−)-nicotine on a percentage basis. The results are reported inTable 1 below.

EXAMPLE 12 Determination of Interaction with Muscle Receptors

The determination of the interaction of the compounds with musclereceptors was carried out in accordance with the techniques described inU.S. Pat. No. 5,597,919 to Dull et al. The maximal activation forindividual compounds (E_(max)) was determined as a percentage of themaximal activation induced by (S)-(−)-nicotine. Reported EC₅₀ values arereported in nM, and E_(max) values represent the amount releasedrelative to (S)-(−)-nicotine on a percentage basis. The results arereported in Table 1 below.

EXAMPLE 13 Determination of Interaction with Ganglion Receptors

The determination of the interaction of the compounds with ganglionicreceptors was carried out in accordance with the techniques described inU.S. Pat. No. 5,597,919 to Dull et al. The maximal activation forindividual compounds (E_(max)) was determined as a percentage of themaximal activation induced by (S)-(−)-nicotine. Reported EC₅₀ values arereported in nM, and E_(max) values represent the amount releasedrelative to (S)-(−)-nicotine on a percentage basis. The results arereported in Table 1 below.

TABLE 1 Sam- Dopamine Muscle Ganglion ple Release Effect Effect No. LogP Ki(nM) EC₅₀ Ec_(max) EC₅₀ Ec_(max) EC₅₀ Ec_(max) 1 1.26 2 2 40 59 1101,100 85 2 2.05 1 2 43 3,000 133 3,000 106 3 0.94 0.5 6 130 100 130 150100 4 0.94 2.5 33 114 100 130 150 100 5 0.93 7 4 93 300 130 N/A 120 60.48 2.6 7 43 3,000 100 10,000 75 7 1.82 1 5 40 700 137 10,000 86 8 1.760.4 31 31 3,000 115 10,000 94 C-1* 0.71 2 115 100 60,000 100 20,000 100*Not an example of the invention. N/A Not available.

The data in Table 1 indicate that the compounds of the present inventionhave the capability to selectively bind with high affinity to certainCNS nicotinic receptors as indicated by their low binding constants, andtheir ability to selectively activate certain CNS receptors and causeneurotransmitter release, as evidenced by dopamine release, therebydemonstrating known nicotinic pharmacology. The data further indicatethat certain compounds activate dopamine release at concentrations wellbelow those concentrations required for activation of muscle organglionic receptors. Thus, the data indicate that the compounds of thepresent invention have the capability of being useful in treating CNSdisorders involving nicotinic cholinergic systems. Furthermore, the dataindicate that certain compounds of the present invention do not causeany appreciable side effects at muscle sites and ganglionic sites atconcentrations effective for producing CNS effects or neurotransmitterrelease, thus indicating a lack of undesirable side effects in subjectsreceiving administration of those compounds at dose ranges at which CNSeffects and neurotransmitter release are elicited.

The data indicate that the compounds of the present invention have thecapability to activate human CNS receptors without activatingmuscle-type or ganglionic-type nicotinic acetylcholine receptors. Thedata show that the compounds of the present invention provide atherapeutic window for utilization in the treatment of CNS disorders.That is, at the levels that the compounds of the present invention areemployed, those compounds show CNS effects and/or neurotransmitterrelease effects to a significant degree but do not show undesirablemuscle or ganglionic effects to any significant degree. The data showthat certain compounds of the present invention, particularly SampleNos. 2, 6 and 8, begin to cause muscle effects and effects upon gangliaonly when employed in amounts of many times those required to causedopamine release.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

That which is claimed is:
 1. A method for treating a disorder characterized by alteration in normal, neurotransmitter release comprising administering to a subject in need thereof an effective, amount of a compound of the general formula:

wherein A, A′, A″ and A′″ individually are substituent species selected from the group consisting of H, halo, R′, —NR′R″, —CF₃, —OH, —CN, —NO₂, —C₂R′, —SH, —SCH₃, —N₃, —SO₂CH₃, —OR′, —SR′, —C(═O)NR′R″, —NR′C(═O)R′, —C(═O)R′, —C(═O)OR′, —(CH₂)_(q)OR′, —OC(═O)R′, —OC(═O)NR′R″ and —NR′C(═O)OR′, R′ and R″ are individually hydrogen, lower alkyl, an aromatic group-containing species, or a substituted aromatic group-containing species, the substituents on the substituted aromatic group-containing species are as identified above with respect to A, A′, A″ and A′″, the aromatic-group containing species is pyridinyl, quinolinyl, pyrimidinyl, phenyl or benzyl, q is an integer from 1 to 6, m, n and p are individually 0, 1 or 2, and the sum of p plus m is 1 or 2, when n is o; j is an integer from 0 to 5, wherein (m+n+p)=1 or 3, R is a non-hydrogen substituent selected from the same group of substituents as listed above with respect to A, A′, A″ and A′″; and the wavy line in, the structure represents that, depending upon the value of each of m, n, p and j, the compound, can have an endo or exo form.
 2. A method for treating a central nervous system disorder comprising, administering to a subject in need thereof, an effective amount of a compound of the general, formula:

wherein A, A′, A″ and A′″ individually are substituent species selected from the group consisting of H, halo, R′, —NR′R″, —CF₃, —OH, —CN, —NO₂, —C₂R′, —SH, —SCH₃, —N₃, —SO₂CH₃, —OR′, —SR′, —C(═O)NR′R″, —NR′C(═O)R′, —C(═O)R′, —C(═O)OR′, —(CH₂)_(q)OR′, —OC(═O)R′, —OC(═O)NR′R″ and —NR′C(═O)OR′, R′ and R″ are individually hydrogen, lower alkyl, an aromatic group-containing species, or a substituted aromatic group-containing species, the substituents on the substituted aromatic group-containing species are as identified above with respect to A, A′, A″ and A′″, the aromatic-group containing species is pyridinyl, quinolinyl, pyrimidinyl, phenyl or benzyl, q is an integer from 1 to 6, m, n and p are individually 0, 1 or 2, and the sum of p plus m is 1 or 2, when n is o; j is an integer from 0 to 5, wherein (m+n+p)=1 or 3, R is a non-hydrogen substituent selected from the same group of substituents as listed above with respect to A, A′, A″ and A′″; and the wavy line in, the structure represents that, depending upon the value of each of m, n, p and j, the compound, can have an endo or exo form.
 3. The method according to claim 1 or 2 wherein j is 0 or
 1. 4. The method according to claim 1 or 2 wherein j is
 0. 5. The method according to claim 1 or 2 wherein m=1, n=0 and p=0.
 6. The method according to claim 1 or 2 wherein m 2, n=1 and p=0.
 7. The method according to claim 1 or 2 wherein m=0, n=1 and p=0.
 8. The method according to claim 1 or 2 wherein m=1, n=1 and p=1.
 9. The method according to claim 1 or 2 wherein m=1, n=2 and p=0.
 10. The method according to claim 1 or 2 wherein A, A′ and A′″ are hydrogen.
 11. The method according to claim 1 or 2 wherein the amount effective to treat said disorder is less than 1 ug/kg patient. 